An aqueous photo-controlled polymerization under NIR wavelengths: synthesis of polymeric nanoparticles through thick barriers

We report an aqueous and near-infrared (NIR) light mediated photoinduced reversible addition–fragmentation chain transfer (photo-RAFT) polymerization system using tetrasulfonated zinc phthalocyanine (ZnPcS4−) as a photocatalyst. Owing to the high catalytic efficiency and excellent oxygen tolerance of this system, well-controlled polyacrylamides, polyacrylates, and polymethacrylates were synthesized at fast rates without requiring deoxygenation. Notably, NIR wavelengths possess enhanced light penetration through non-transparent barriers compared to UV and visible light, allowing high polymerization rates through barriers. Using 6.0 mm pig skin as a barrier, the polymerization rate was only reduced from 0.36 to 0.21 h−1, indicating potential for biomedical applications. Furthermore, longer wavelengths (higher λ) can be considered an ideal light source for dispersion photopolymerization, especially for the synthesis of large diameter (d) nanoparticles, as light scattering is proportional to d6/λ4. Therefore, this aqueous photo-RAFT system was applied to photoinduced polymerization-induced self-assembly (photo-PISA), enabling the synthesis of polymeric nanoparticles with various morphologies, including spheres, worms, and vesicles. Taking advantage of high penetration and reduced light scattering of NIR wavelengths, we demonstrate the first syntheses of polymeric nanoparticles with consistent morphologies through thick barriers.


Introduction
Photoinduced reversible deactivation radical polymerization (photo-RDRP) 1-58 techniques enable the production of polymers with low dispersity and dened architectures and provide a high degree of spatio-temporal reaction control. As a useful photo-RDRP variant, photoinduced reversible addition-fragmentation chain transfer polymerization (photo-RAFT) polymerization process  oen uses ppm range photocatalysts (PCs) to activate RAFT agents under visible light without the need for deoxygenation. [48][49][50][51][52] Although photo-RDRP systems that use visible light (l ¼ 400-700 nm) are well-established, systems regulated by near-infrared light (NIR, l ¼ 700-2500 nm) are still rare. [20][21][22][23][24][25][26][43][44][45][46][47] This is mainly due to the difficulty in using long wavelength, low energy (E ¼ h/l) irradiation to drive photochemical reactions. 59 While PCs with NIR light absorption exist, they commonly possess lower redox potentials of excited state (S 1 and T 1 ), resulting in limited catalytic performance and inability to mediate photoinduced electron/energy transfer (PET) processes. 43 However, compared to shorter wavelengths, NIR light has enhanced penetration through non-transparent barriers, 60 which can be benecial for materials engineering and potential biomedical applications. For instance, transdermal photopolymerization has been employed for injectable hydrogel systems, minimizing operative wounds and conferring spatiotemporal control towards gelation. [61][62][63] Meanwhile, using aqueous media instead of organic solvents for polymerizations provides economic and environmental benets, further increasing these systems for bio-applications. 50,[61][62][63][64] However, long-wavelength-mediated aqueous photo-RDRP systems have seldom been reported, 17,20,51 due to the typically low solubility of NIR absorbing catalysts in aqueous media. In 2020, Qiao and co-workers developed an aqueous visible-and NIR-mediated photoinduced electron/energy transfer reversible addition-fragmentation chain transfer (PET-RAFT) polymerization process catalyzed by a selfassembled carboxylated porphyrin photocatalyst. 51 However, this system suffers from low polymerization rates under NIR irradiation and provided only low monomer conversions without deoxygenation. Recently, the groups of Pan and Pang reported the successful utilization of upconversion nanoparticles as heterogeneous photocatalysts to induce photoinduced atom-transfer radical polymerizations (photo-ATRP) under NIR laser light in aqueous media. 17,20 Nevertheless, prior deoxygenation and high-intensity light sources were required in these systems to achieve appreciable monomer conversions.
In this study, aqueous photo-RAFT systems catalyzed by tetrasulfonated zinc phthalocyanine (ZnPcS 4 À ) under NIR light irradiation (l max ¼ 730 nm) were successfully developed. ZnPcS 4 À has been used widely as a photosensitizer in photodynamic therapy (PDT) owing to its absorption of extended wavelengths and excellent solubility in water, [65][66][67][68][69][70] however, this is the rst example of ZnPcS 4 À as a PC to mediate photopolymerization. These aqueous systems exhibited excellent oxygen tolerance, providing high polymerization rates and polymers with narrow molecular weight distributions (MWDs). Taking advantage of the enhanced penetration of NIR light, photopolymerizations were performed with non-transparent barriers between the light source and the reaction vessel, resulting in high polymerization rates (0.21-0.34 hour À1 ) and well-dened polymers (dispersity (Đ) < 1.15). Although photopolymerization through barriers has been demonstrated in previous NIR light mediated RDRP systems, [21][22][23][44][45][46]51 this is the rst aqueous system which displays fast polymerization in the presence of thick barriers and does not require deoxygenation. Aqueous media and excellent oxygen tolerance facilitate the potential application of this NIR system in materials engineering and biomedicine. 50,[61][62][63][64] In addition, the developed polymerization systems are highly suited for aqueous polymerization-induced self-assembly (PISA) as they do not require deoxygenation, which simplies the synthetic procedure. More importantly, long wavelength (l) NIR light is an ideal energy source to perform photoinitiated polymerization-induced self-assembly (photo-PISA), 71-82 especially for synthesizing large (d) nanoparticles, as light scattering is directly proportional to d 6 /l 4 . [83][84][85][86][87] Reduced scattering diminishes light intensity gradients in the reaction media, promoting light penetration in colloidal dispersions, which can favor the production of polymeric nanoparticles with more well-dened morphologies. Photo-RAFT mediated aqueous dispersion polymerization of 2-hydroxypropyl methacrylate (HPMA) was conducted using a poly(ethylene glycol) (PEG) functionalized RAFT agent as the rst stabilizing block. As a result, nanoparticles with various morphologies, including spheres, worms, and vesicles, were successfully synthesized by simply changing the targeted degree of polymerization (DP). Furthermore, polymeric nanoparticles with consistent morphologies were synthesized via photo-PISA through a biological barrier (6.0 mm thick pig skin). To our knowledge, this is the rst example of polymeric nanoparticle synthesis through thick barriers using NIR light. Like the barrier-free photo-PISA, we observed a similar evolution of nanoparticle morphologies, i.e., from spheres to vesicles, when a biological barrier was introduced. The successful synthesis of large vesicles ($200 nm diameter) through thick barriers indicated the high efficiency of this system.     formation of H 2 O 2 was detected aer 3 hours in the presence of ZnPcS 4 À and TEOA under NIR light irradiation (ESI, Fig. S4E †).

Results and discussion
Without deoxygenation, similar results were obtained in the absence of ZnPcS 4 À or light (ESI, Fig. S4D (Fig. 1A, #1; ESI, Scheme S1A †) using water and DMF as the solvent. DMF was used to increase the solubility of 9,10-DMA and replace the monomer in our system. Under irradiation, we observed a decrease of 9,10-DMA signals between 330 and 420 nm (Fig. 1A, #2) (Fig. 1B, #1). Indeed, NBT reacts with O 2 c À (ESI, Scheme S1B †) to yield monoformazan (MF; l max at $525 nm) and diformazan (DF; l max at $740 nm). 98 In the absence of TEOA, no absorptions of characteristic MF and DF signals were observed, indicating the absence of O 2 c À formation (Fig. 1B, #2). In contrast, two characteristic signals of MF and DF appeared when TEOA was added to the mixture, suggesting O 2 c À generation (Fig. 1B, #3). Additionally, a faster increase in absorption of MF and DF was observed when a higher ratio of TEOA was added ( In addition to experimental evidence, a series of densityfunctional theory (DFT) calculations were performed to calculate the Gibbs free energy change (DG) for the three different reaction pathways (Scheme 2). The reaction step possessing a lower value of DG indicates a more favorable electron transfer. DG values of each reaction involved with electron transfer are listed in Scheme 2. In this work, PET-RAFT polymerization via RQP is more favorable than OQP, showing lower values of DG (11.1 kcal mol À1 for RQP-I and 7.0 kcal mol À1 for RQP-II versus OQP-I ¼ 17.5 kcal mol À1 ). This is in agreement with the faster polymerization rate measured in PET-RAFT polymerization via RQP than OQP (0.08 hour À1 versus 0.01 hour À1 in ESI, Fig. S2 †). Furthermore, DG of the electron transfer from TEOA to 1 O 2 in O-PI pathway was calculated as À16.1 kcal mol À1 , which is signicantly more favorable than the activation steps both in OQP and RQP. This computational result conrms our experimental observation that O-PI displays signicantly faster polymerization (ESI, Fig. S2 †) Fig. S11, blue line; Table S3, † #3), which can be attributed to limiting light penetration in the system due to the absorption of ZnPcS 4 À .
To demonstrate the versatility of this PC to activate different RAFT agents, three other RAFT agents, including 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid (CDTPA), 2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid (DDMAT), and 2-(butylthiocarbonothioylthio)propanoic acid (BTPA) (Scheme 1B), were tested in this aqueous system using a relatively high monomer concentration (50 v% (49 wt%)) in water, to enable the solubilization of these RAFT agents. Compared to BTPA-mediated photopolymerization (ESI, Fig. S12, red line; Table S4, † #4), CDTPA and DDMAT (ESI, Fig. S12, orange and blue lines; Table S4, † #2 and 3) displayed faster polymerization rates and better control. This can be attributed to favorable activation of the tertiary R group of CDTPA and DDMAT than the secondary R group of BTPA. 43,101,102 Moreover, owing to the better water-solubility of CTCPA than CDTPA and DDMAT, a faster polymerization rate and narrower MWD of synthesized PDMA were also observed in the presence of CTCPA (ESI, Fig. S12A, green line; Table S4, † #1). In summary, the optimal polymerization condition was estab- Temporal control of this aqueous photo-RAFT polymerization was demonstrated ( Fig. 2A)  , and as a consequence, did not form radicals to initiate the photopolymerization. An excellent agreement between M n,theo and M n,GPC and a decreasing Đ from 1.2 to 1.1 were observed during the polymerization (Fig. 2B). Moreover, the MWDs of synthesized PDMA shied toward higher molecular weight with increasing irradiation time (Fig. 2C), conrming the controlled character of this aqueous photo-RAFT polymerization. To conrm the maintenance of trithiocarbonate at the end of the polymerization, PDMA was successfully chain extended by adding fresh DMA, leading to clear shis of MWDs of PDMA-b-PDMA (Fig. 2D). Similar results were obtained when poly(oligo(ethylene glycol)methyl ether methacrylate) (POEGMA) was chain extended in the presence of DMA to yield POEGMA-b-PDMA block copolymers (ESI, Fig. S13 †). Similar to photopolymerizations performed aer deoxygenation (ESI, Fig. S14B †), the high end group delity of polymers synthesized in the presence of oxygen was also conrmed by 1 H NMR spectroscopy (ESI, Fig. S14A †). Signals at 5.1 ppm attributed to the CH adjacent to the trithiocarbonate on the R-group side remained in a similar ratio to the CH 3 protons from the n-butyl Zgroup under both deoxygenated and non-deoxygenated conditions. Subsequently, the degrees of polymerization (DPs) varied from 100 to 800 (ESI , Table S5 and Fig. S15 †), resulting in the preparation of PDMA with narrow and symmetric MWDs (Đ < 1.2). To investigate the versatility of this system toward various monomers, we decided to expand the family and type of watersoluble monomers (ESI , Table S6

Aqueous photo-RAFT polymerizations through various barriers under NIR light
Notably, compared with UV and visible light, longer wavelengths, such as NIR light, have enhanced penetration through nontransparent materials, making photopolymerization feasible to conduct through thick barriers (ESI, Fig. S17 †). A series of photopolymerizations catalyzed by ZnPcS 4 À was performed through various barriers without prior deoxygenation. In the presence of 0.1 and 0.2 mm print paper, although k p app decreased from 0.36 to 0.26 and 0.21 hour À1 (ESI, Fig. S18A †), polymers were successfully synthesized in a controlled manner (ESI , Table S7, †  #2 and 3). In addition, biological barriers, such as pig skin, were tested in this system. K p app declined slightly from 0.36 to 0.34 hour À1 (ESI, Fig. S18B, † blue line) when 1.5 mm pig skin was used as the barrier between the NIR LED light and the reaction mixture. When the thickness of pig skin increased further to 3.0 mm, a decrease in k p app was noted as 0.27 hour À1 (Fig. 3D, orange   line). Surprisingly, through the 6.0 mm thickness of pig skin, a relatively fast k p app of 0.21 hour À1 was still achieved in this long wavelengths mediated system (Fig. 3D, red Fig. S19 †).
To emphasize the enhanced penetration of NIR light through non-transparent barriers compared to visible light (400-700 nm), the light intensity of various wavelengths (violet light, l max ¼ 405 nm; green light, l max ¼ 530 nm; NIR light l max ¼ 730 nm) were measured before and aer passing through barriers with different thicknesses (Fig. 3A). Through 3.0 mm pig skin, the light intensity (I) of violet light decreased to 0.2% of the initial value (I 0 ). While green light was less attenuated than violet light, the light intensity still dropped to only 1.7% of the original I 0 value aer passing through 3.0 mm pig skin. In contrast to the limited light penetration of these shorter wavelengths, 730 nm light was able to penetrate through the barriers in appreciable quantities, with 30.7% and 14.7% of the initial light passing through 3.0 and 6.0 mm pig skin, respectively.
To compare the photopolymerization performance between the visible light mediated system and the NIR light mediated system through barriers, zinc meso-tetra(N-methyl-4-pyridyl) porphine tetrachloride (ZnTMPyP; Fig. S20 †) was employed as a model PC owing to its water solubility and broad absorption in visible regions 50 (ESI , Table S8 and Fig. S21 †). Under violet (l max ¼ 405 nm) and green (l max ¼ 530 nm) light irradiation and in the absence of barriers, photo-RAFT polymerization catalyzed by ZnTMPyP displayed signicantly fast polymerization rates ( Fig. 3B and C, 6.30 h À1 under violet light and 0.93 h À1 under green light), which is much faster than NIR light system (0.36 h À1 ) under similar light intensities (I violet ¼ 45 mW cm À2 ; I green ¼ 72 mW cm À2 ; I NIR ¼ 60 mW cm À2 ). However, in the presence of 3.0 mm pig skin as the barrier, polymerization under violet light showed no monomer conversion aer 3 hours (Fig. 3B). Meanwhile, a very long induction period (2 hours) and a slow polymerization rate (0.07 h À1 ) were noted when green light was employed (Fig. 3C). In contrast to violet and green light systems, photo-RAFT mediated by NIR light under NIR showed a slight decrease in k p app from 0.36 to 0.27 h À1 (Fig. 3D) when a 3 mm pig skin was introduced. Aqueous photo-PISA catalyzed by ZnPcS 4 À under NIR light in the presence of oxygen Inspired by the monomer versatility and oxygen tolerance, this aqueous photo-RAFT polymerization system was applied to photoinitiated polymerization-induced self-assembly (photo-PISA) to synthesize polymeric nanoparticles. Notably, light scattering limits the light penetration through a dispersion polymerization reaction according to the Rayleigh light scattering equation (proportional to d 6 /l 4 ), where d is the diameter of the particles and l is the wavelength of incident light. Therefore, longer wavelengths of irradiation are more suitable to mediate photoinduced dispersion polymerization, especially for synthesizing large nanoparticles.
In this work, PEG 113 -CDTPA macromolecular RAFT agent was used as the rst stabilizing block, and the chains were extended in the presence of hydroxypropyl methacrylate (HPMA) as the coreforming monomer in this aqueous photo-RAFT dispersion polymerization (Scheme 1B and Fig. 4A). Optimization experiments with various ratios of TEOA (ESI,  , Table S2, † #2: 53% monomer conversion in 3 hours), a limited monomer conversion (8% monomer conversion in 24 hours) was observed in dispersion photopolymerization using this ratio (ESI , Table S9 † #2). This was attributed to the lower monomer content used in dispersion polymerization in contrast to homogenous polymerization (20 wt% versus 50 v% (49 wt%)). As [TEOA] : [PEG 113 -CDTPA] increased further to 4 : 1, monomer conversion reached 99% in 24 hours as indicated by 1 H NMR spectroscopy (ESI, Fig. S22 †). GPC analysis conrmed successful chain extension of PEG 113 -CDTPA and the preparation of narrow molecular weight diblock copolymers (ESI, Fig. S23 †).
Subsequently, the kinetics study of ZnPcS 4 À mediated photo- (micellization). To conrm this assumption, transmission electron microscopy (TEM) was performed at different time points (t ¼ 5, 6, and 7 hours). At t ¼ 5 hours, the early stage of the micellization was conrmed by the presence of spherical nanoparticles with $20 nm diameter and short worms (Fig. 4E). As the photopolymerization continued, the morphologies of nanoparticles evolved from a mixture of spheres and worms to worms and vesicles (Fig. 4F). At the nal point of the kinetics (92% monomer conversion at t ¼ 7 hours), pure vesicles with $250 nm diameter were observed (Fig. 4G). This evolution in morphology was supported by the apparent change from a transparent solution to a cloudy (milky) solution ( Fig. 4E-G, photos at right bottom). In addition, the size distribution of these particles increased with higher monomer conversions, as indicated by dynamic light scattering (DLS) analyses (ESI , Table  S10 and Fig. S24 †). Moreover, this aqueous dispersion polymerization was performed in a controlled manner, as indicated by the analysis of the diblock copolymers by GPC (Fig. 4C and D). We observed a good agreement between M n,GPC and M n,theo and relatively low MWD (Đ < 1.4). Concerning Đ, a decrease was observed rst from 1.27 to 1.14 before the micellization (Fig. 4C), which can be attributed to the photoactivation of PEG 113 -CDTPA macroRAFT agent to PEG 113 -b-PHPMA with increasing irradiation time as indicated by GPC analyses (Fig. 4D: 0, 2, 4, and 5 hours). Aer that, Đ increased gradually from 1.14 to 1.36 in the phase of dispersion polymerization (Fig. 4C, last three red triangle points). In addition, a clear shi of MWDs towards higher molecular weight with increasing reaction time was observed (Fig. 4D) in this photo-PISA system, indicating the living characters of synthesized polymers.

Morphological evolution of synthesized nanoparticles with different targeted DPs and solids content
This aqueous and oxygen tolerant photo-PISA system was investigated further with various targeted DPs at 20 wt% solids content aer reaching high monomer conversions (>95%). Overall, dispersion polymerization targeting lower DPs exhibited closer values between M n,GPC and M n,theo (Fig. 5A), resulting in the synthesis of PEG 113 -b-PHPMA with narrower MWDs than polymerization with higher DPs (ESI, Fig. S25 †). The reactions ranging from 100 to 300 DPs were signicantly viscous, as shown by the digital photos of vials (Fig. 5B), which is likely to correspond to the formation of worms morphologies. Meanwhile, appearances of increasingly cloudy reactions were observed in the reactions with higher targeted DPs, especially for 250, 300, and 350 DPs (Fig. 5B). This indicated that largersize nanoparticles were prepared with higher DPs, which was also conrmed by DLS measurements (ESI, Table S13, #9-12; Fig. S28C †). Furthermore, TEM was carried out to observe the morphologies for these nanoparticles with different DPs (Fig. 5C). First, a mixture of the majority of spheres and the minority of short worms (S/W) was observed with 100 DP (Fig. 5C, top rst). With increasing DPs to 150 and 200, the population of nanoparticles evolved into worms (major) and spheres (minor) (W/S; Fig. 5C, top second and third). Among these two DPs, much longer worms were observed in 200 DP (Fig. 5C, top third) than in 150 DP. Moreover, the morphology of pure worms (W) was observed in the dispersion polymerization with 250 DP (Fig. 5C, top fourth). As the targeted DP increased to 300, a mixed morphology appeared again, consisting of worms and some vesicles (W/V; Fig. 5C, bottom rst). As DPs increased further from 350 to 450, we observed pure vesicles with increasing sizes from $200 to $500 nm (Fig. 5C, bottom  last three).
The evolution of the morphology was also studied at 10 and 15 wt% solids concentration by varying DPs from 100 to 400. A phase diagram was plotted, reecting the morphologies of these nanoparticles versus various DPs and solids content (Fig. 6A). At 10 wt% solids content, although the morphologies of synthesized PEG 113 -b-PHPMA did not show any transformation with increasing DPs, we observed an apparent increase of spherical nanoparticle sizes from $25 nm at 100 DP to $56 nm at 400 DP (Fig. 6B, bottom row). In contrast to 10 wt%, the change in morphology at 15 wt% solids concentration was similar to 20 wt%, evolving from S/W to V with increasing DPs. On the other hand, there are size differences of synthesized nanoparticles between 15 wt% (Fig. 6B, top row) and 20 wt% (Fig. 5C), which can be easily observed in TEM and DLS analyses (ESI , Table S13 and Fig. S28 †). For an example of 400 DP, the diameter of synthesized vesicles at 15 wt% was $200 nm, while at 20 wt% solids concentration, the size was $400 nm. Overall, a phase diagram was successfully plotted in this photo-PISA system (Fig. 6A), facilitating the nanoparticle synthesis with specic morphologies and sizes under NIR light irradiation. Furthermore, PEG 113 -b-PHPMA copolymers forming the nanoparticles displayed narrow MWDs (ESI, Fig. S26 and S27 †) and a good correlation between M n,GPC and M n,theo (ESI, Tables S11 and S12 †).

Synthesis of polymeric nanoparticles through thick barriers under NIR wavelengths
As demonstrated previously in homogenous photopolymerizations, longer wavelengths possess enhanced penetration through non-transparent materials, enabling the synthesis of polymers through thick barriers. Photopolymerization through barriers can be considered more challenging in dispersion polymerization than in the homogenous solution, due to the light scattering of particles impeding the light penetration through the reaction media. As the homogenous photo-RAFT process exhibited high efficiency using 6.0 mm pig skin as the barrier (Fig. 3), this thickness of pig skin was selected in the photo-PISA system (Fig. 7A). Compared to barrier-free photopolymerization, k p app declined slightly from 0.072 to 0.044 hour À1 before micellization (0-7 hours) in the presence of the pig skin barrier (Fig. 7B). Aer micellization (7-12 hours), k p app decreased more signicantly from 1.003 (without barrier) to 0.343 hour À1 (with barrier), which was attributed to the presence of light scattering due to the formation of the nanoparticles. However, the evolution of nanoparticle morphologies was not affected by the inclusion of this barrier. At t ¼ 7 hours (33% monomer conversion), PEG 113 -b-PHPMA exhibited a mixed morphology consisting of spheres and worms (Fig. 7C), which evolved to pure worms (Fig. 7D) under light irradiation for additional two hours. At 12 hours, TEM indicated the formation of vesicles with $200 nm diameter ( Fig. 7E). Moreover, this photoinduced dispersion polymerization system enabled the synthesis of well-dened polymers through thick barriers, showing a linear relationship between M n,GPC and monomer conversion (ESI, Fig. S29 †).

Conclusion
ZnPcS 4 À was demonstrated as an efficient photocatalyst to mediate aqueous photo-RAFT polymerization under NIR light irradiation, enabling the synthesis of various polymers (polyacrylamide, polyacrylate, and polymethacrylate) in a controlled manner without the need for prior deoxygenation. Owing to the enhanced penetration capabilities afforded by NIR wavelengths, photopolymerizations were successfully conducted through thick barriers at fast polymerization rates in the presence of air. As longer wavelengths display less light scattering, this aqueous and NIR light mediated system was applied in the photo-PISA system, enabling the successful preparation of polymeric nanoparticles with consistent morphologies in water. Moreover, an evolution from spheres to vesicles was observed with increasing monomer conversion in the kinetics study. By plotting a phase diagram of this photo-PISA system, the targeted synthesis of polymeric nanoparticles with specic morphologies and sizes was accessible. Notably, polymeric nanoparticles with precise morphologies were successfully synthesized through 6.0 mm pig skin under NIR light irradiation, owing to enhanced light penetration and reduced light scattering afforded by long wavelengths.

Data availability
All data associated with this article have been included in the main text and ESI. †

Conflicts of interest
The authors declare no conict of interest.